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. 2016 Mar 21;7:10967.
doi: 10.1038/ncomms10967.

Genome-wide DNA Methylation Levels and Altered Cortisol Stress Reactivity Following Childhood Trauma in Humans

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Free PMC article

Genome-wide DNA Methylation Levels and Altered Cortisol Stress Reactivity Following Childhood Trauma in Humans

Lotte C Houtepen et al. Nat Commun. .
Free PMC article

Abstract

DNA methylation likely plays a role in the regulation of human stress reactivity. Here we show that in a genome-wide analysis of blood DNA methylation in 85 healthy individuals, a locus in the Kit ligand gene (KITLG; cg27512205) showed the strongest association with cortisol stress reactivity (P=5.8 × 10(-6)). Replication was obtained in two independent samples using either blood (N=45, P=0.001) or buccal cells (N=255, P=0.004). KITLG methylation strongly mediates the relationship between childhood trauma and cortisol stress reactivity in the discovery sample (32% mediation). Its genomic location, a CpG island shore within an H3K27ac enhancer mark, and the correlation between methylation in the blood and prefrontal cortex provide further evidence that KITLG methylation is functionally relevant for the programming of stress reactivity in the human brain. Our results extend preclinical evidence for epigenetic regulation of stress reactivity to humans and provide leads to enhance our understanding of the neurobiological pathways underlying stress vulnerability.

Conflict of interest statement

C.B.N.'s work has been funded by the NIH. He is a member of the scientific advisory board of the American Foundation for Suicide Prevention (AFSP), Brain & Behavior Research Foundation (BBRF), Xhale, Anxiety Disorders Association of America (ADAA), Skyland Trail, Clintara LLC and RiverMend Health LLC, and has received income sources or equity of $10,000 or more from American Psychiatric Publishing, Xhale and Clintara. He is also a member of the board of directors of the AFSP, Gratitude America and ADAA and has consulted for Xhale, Takeda, SK Pharma, Shire, Roche, Lilly, Allergan, Mitsubishi Tanabe Pharma Development America, Taisho Pharmaceutical Inc., Lundbeck, Prismic Pharmaceuticals, Clintara LLC and Total Pain Solutions (TPS). C.H.V. is an advisor for DynaCorts. M.P.M.B., T.C.-R., M.H., P.v.L., W.M., S.B., C.M.H., J.M., L.C.S., M.P.C., R.S.K., M.J., E.B.B. and L.C.H. declare no potential conflict of interest.

Figures

Figure 1
Figure 1. Flowchart of the main analysis.
First we performed a genome-wide analysis of the association between cortisol stress reactivity and DNA methylation in the discovery sample (N=85). On the basis of the P value distribution, we sought replication of the top three loci in two independent samples (N=45/N=255) and replicated the negative association between the top KITLG locus and cortisol stress reactivity. Then we investigated the influence of childhood trauma on KITLG methylation and cortisol stress reactivity in the discovery and blood replication sample. On finding an association for childhood trauma with KITLG methylation and cortisol stress reactivity in the discovery sample and Caucasian of the blood replication sample, we examined whether the KITLG locus is a mediator for the blunted cortisol stress response after childhood trauma exposure.
Figure 2
Figure 2. The association between cortisol stress reactivity and DNA methylation at the KITLG/cg27512205 locus in the discovery (top panel), blood replication (middle panel) and cross-tissue replication (bottom panel) samples.
A linear regression line is plotted through the individual methylation values.
Figure 3
Figure 3. Correlation between childhood trauma (total CTQ score) and cortisol stress reactivity (AUCi) in the discovery and replication sample.
Colour indicates methylation levels at the cg27512205 (KITLG) locus. In the replication sample (right panel) differences in ethnicity are visualized. AUCi, area under the curve (AUC) with respect to the increase; CTQ, Childhood Trauma Questionnaire.
Figure 4
Figure 4. Model used to investigate mediation by the KITLG locus in the discovery sample.
For graphical representation only, we did not add the sex and age covariates that were included in all statistical analyses.
Figure 5
Figure 5. Overview of the 1,500 base pair area downstream and upstream of the cg27512205 KITLG locus.
The top panel contains the −log P values for the association between DNA methylation and cortisol stress reactivity in the discovery (blue, N=85), blood replication (black, N=45) and cross-tissue replication (magenta, N=255) samples per locus (total of 14 loci in the depicted area). The other panels indicate the presence of coding exons (blue blocks) and non-coding introns (grey line) of the KITLG gene (second panel), location of a CpG island (third panel) and the percentage of G (guanine) and C (cytosine) bases (fourth panel) in the area around the cg27512205 locus extracted from the UCSC website with the Gviz R package. The bottom panel indicates the location of a H3K27ac histone modification in lateral hypothalamus tissue (data from ref. 22). Our locus of interest is shaded across all panels by a red rectangle. In the top panel all points above the horizontal dashed grey line are nominally associated (P<0.05) loci in a linear regression model. chr, chromosome.
Figure 6
Figure 6. Graphical depiction of the connection between the KITLG-related probe and its direct neighbours within the red module (Supplementary Data 2).
The node size indicates the association with cortisol stress reactivity, while the width of the lines indicates the connection strength between the nodes.

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